article · Nature · 2024
Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
Ken Suzuki, Konstantinos Hatzikotoulas, Lorraine Southam, Henry J. Taylor, Xianyong Yin, Kimberly Lorenz, Ravi Mandla, Alicia Huerta‐Chagoya, Giorgio Melloni, Stavroula Kanoni, Nigel W. Rayner, Ozvan Bocher, Ana Luiza Arruda, Kyuto Sonehara, Shinichi Namba, Simon Lee, Michael Preuß, Lauren E. Petty, Philip Schroeder, Brett Vanderwerff, Mart Kals, Fiona Bragg, Kuang Lin, Xiuqing Guo, Weihua Zhang, Jie Yao, Young Jin Kim, Mariaelisa Graff, Fumihiko Takeuchi, Jana Nano, Amel Lamri, Masahiro Nakatochi, Sanghoon Moon, Robert A. Scott, James P. Cook, Jung‐Jin Lee, Ian Pan, Daniel Taliun, Esteban J. Parra, Jin Fang Chai, Lawrence F. Bielak, Yasuharu Tabara, Yang Hai, Guðmar Þorleifsson, Niels Grarup, Tamar Sofer, Matthias Wuttke, Chloé Sarnowski, Christian Gieger, Darryl Nousome and 319 more
Cited by 445Open access
Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes<sup>1,2</sup> and molecular mechanisms that are often specific to cell type<sup>3,4</sup>. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10<sup>-8</sup>) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores<sup>5</sup> in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
Cite this paper
Suzuki, K., Hatzikotoulas, K., Southam, L., Taylor, H. J., Yin, X., Lorenz, K., Mandla, R., Huerta‐Chagoya, A., Melloni, G., Kanoni, S., Rayner, N. W., Bocher, O., Arruda, A. L., Sonehara, K., Namba, S., Lee, S., Preuß, M., Petty, L. E., Schroeder, P., . . . Nousome, D. (2024). Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627(8003), 347–357. https://doi.org/10.1038/s41586-024-07019-6
Suzuki, Ken, et al. “Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.” Nature, vol. 627, no. 8003, 2024, pp. 347–57, https://doi.org/10.1038/s41586-024-07019-6.
Suzuki, Ken, Konstantinos Hatzikotoulas, Lorraine Southam, Henry J. Taylor, Xianyong Yin, Kimberly Lorenz, Ravi Mandla, et al. 2024. “Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.” Nature 627 (8003): 347–57. https://doi.org/10.1038/s41586-024-07019-6.
Suzuki, K. et al. (2024) ‘Genetic drivers of heterogeneity in type 2 diabetes pathophysiology’, Nature, 627(8003), pp. 347–357. Available at: https://doi.org/10.1038/s41586-024-07019-6.
@article{suzuki2024genetic,
title = {{Genetic drivers of heterogeneity in type 2 diabetes pathophysiology}},
author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J. and Yin, Xianyong and Lorenz, Kimberly and Mandla, Ravi and Huerta‐Chagoya, Alicia and Melloni, Giorgio and Kanoni, Stavroula and Rayner, Nigel W. and Bocher, Ozvan and Arruda, Ana Luiza and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon and Preuß, Michael and Petty, Lauren E. and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A. and Cook, James P. and Lee, Jung‐Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J. and Chai, Jin Fang and Bielak, Lawrence F. and Tabara, Yasuharu and Hai, Yang and Þorleifsson, Guðmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloé and Gieger, Christian and Nousome, Darryl and others},
journal = {Nature},
volume = {627},
number = {8003},
pages = {347--357},
year = {2024},
doi = {10.1038/s41586-024-07019-6}
}Made from the index record. Check names, capitalisation and page numbers against the paper. Need another style? AI for Research has over 10,000.